Formulation of a PCNA inhibitor

Abstract

Described herein, inter alia, are formulations of a PCNA inhibitor and methods using the same.

Description

PATENT Attorney Docket No.: 048440-208001WO FORMULATION OF A PCNA INHIBITOR CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 707,581 filed October 15, 2024, which is incorporated herein by reference in its entirety and for all purposes. BACKGROUND

[0002] Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes and it is also a proliferation biomarker in a variety of human tumors. A unique cancer-associated isoform of the protein, caPCNA, has been previously identified that potentially allows for selective therapeutic targeting of cancer cells. A number of strategies have been employed to develop agents targeting caPCNA, including peptide and small molecule-based inhibitors, but the success in developing therapeutically tractable compoundshas been limited. Disclosed herein, inter alia, are solutions to these and other problems in theart. BRIEF SUMMARY

[0003] In an aspect is provided a pharmaceutical composition including a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof. Inacceptable excipient is hydroxypropyl methylcellulose.

[0004] In an aspect is provided a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula:a pharmaceutically acceptable salt thereof; wherein the s 150 mg; and wherein the pharmaceutical composition is in a tablet form suitable for human oral administration.

[0005] In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject the pharmaceutical composition described herein, including in embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG.1. Two-step dissolution profile for three ASDs.

[0007] FIG.2. Process flow diagram of 150 mg AOH1996 tablets. IPC = in-process testing; PSD = particle size distribution; BD = bulk density; TD = tapped density; LOD = loss on drying.

[0008] FIG.3. Process flow diagram of GMP batch SDD.

[0009] FIG.4. Pharmacokinetic (PK) profiles of AOH1996 in patients.

[0010] FIG.5. Comparison of PK properties of the tablet and softgel formulations. DETAILED DESCRIPTION I. Definitions

[0011] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0012] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0013] As used herein, the term “crystalline” or “crystalline state” or “crystalline form” means having a physical state that is a regular three-dimensional array of atoms, ions, molecules, or molecular assemblies. Crystalline states have lattice arrays of building blocks that are arranged according to well-defined symmetries into unit cells that are repeated in three dimensions. In contrast, the term “amorphous” or “amorphous state” or “amorphous form” refers to a non-crystalline solid state. The physical state of a compound may be determined by techniques such as X-ray powder diffraction, polarized light microscopy and / or differential scanning calorimetry.

[0014] A compound, salt form, crystal polymorph, therapeutic agent, or other composition described herein may be referred to as being characterized by graphical data “substantially as depicted in” a figure. Such data may include, but is not limited to, X-ray powder diffraction spectra, NMR spectra, differential scanning calorimetry curves, and thermogravimetric analysis curves, among others. As is known in the art, such graphical data may provide additional technical information to further define the compound, salt form, crystal polymorph, therapeutic agent, or other composition. As is understood by one skilled in the art, such graphical representations of data may be subject to small variation, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity.

[0015] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic,malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0016] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

[0017] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0018] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0019] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0020] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0021] The terms “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. For example, the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer and or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. For example, certain methods herein treat diseases associated with PCNA activity. Certain methods described herein may treat diseases associated with PCNA activity (e.g., cancer) by inhibiting PCNA activity. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.

[0022] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0023] “Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison inevaluating experimental effects. In some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).

[0024] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0025] The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments, contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.

[0026] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0027] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

[0028] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments, inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.

[0029] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0030] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0031] The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effectsof a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0032] “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

[0033] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is cancer (e.g., sarcoma, adenocarcinoma, leukemia, or lymphoma).

[0034] As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include, Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer,hepatocellular carcinoma, or prostate cancer.

[0035] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0036] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma,diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0037] The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing’s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0038] The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

[0039] The term “carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cellcarcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0040] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred toas a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

[0041] The terms “cutaneous metastasis” and “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.

[0042] The term “visceral metastasis” refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.

[0043] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug.

[0044] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0045] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. The compounds of the invention can be administered alone or can be co-administered to the patient. Co- administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0046] “Co-administer” is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0047] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. A daily dose range of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, can be used. The dosages, however,may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., cancer) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0048] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., cancer) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, a disease associated with PCNA activity may be treated with an agent (e.g., compound as described herein) effective for decreasing the level of PCNA activity.

[0049] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0050] The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety(monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

[0051] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0052] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0053] The term “Proliferating cell nuclear antigen” or “PCNA” refers to a ~29 kDa protein that self assembles into a protein complex consisting of 3 subunits of individual PCNA proteins. Together these joined PCNA molecules form a DNA clamp that acts as a processivity factor for DNA polymerase ^ in eukaryotic cells. The term “PCNA” may refer to the nucleotide sequence or protein sequence of human PCNA (e.g., Entrez 5111, Uniprot P12004, RefSeq NM_002592, or RefSeq NP_002583). The term “PCNA” includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof. In some embodiments, “PCNA” is wild-type PCNA. In some embodiments, “PCNA” is one or more mutant forms. The term “PCNA” XYZ refers to a nucleotide sequence or protein of a mutant PCNA wherein the Y numbered amino acid of PCNA that normally has an X amino acid in the wild-type, instead has a Z amino acid in the mutant. In embodiments, a PCNA is the human PCNA. In embodiments, the PCNA has the nucleotide sequence corresponding to reference number GI:33239449. In embodiments, the PCNA has the nucleotide sequence corresponding to RefSeq NM_002592.2. In embodiments, the PCNA has the protein sequence corresponding to reference number GI:4505641. In embodiments, the PCNA has the nucleotide sequence corresponding to RefSeq NP_002583.1. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.

[0054] In embodiments, the PCNA is a mutant PCNA. In embodiments, the mutant PCNA is associated with a disease that is not associated with wild-type PCNA. In embodiments, thePCNA includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to the sequence above. PCNA may be post-translationally modified. Modifications may include phosphorylation, methylation, methylesters of acidic amino acids, ribosylation, acetylation, glycosylation with a variety of sugars, lipidation with a variety of different lipids, poly(ADP) ribosylation, or other post-translational modifications known in the art. Differences in the extent and type of modification influences the levels (e.g., protein levels) of the ca- and nm- PCNA isoforms. In embodiments, a post-translational modification or plurality of post- translational modifications modify the inhibition of PCNA by a compound described herein or the binding of a compound described herein to PCNA, relative to PCNA without the post- translational modification(s).

[0055] The terms “cancer-associated proliferating cell nuclear antigen” or “caPCNA” as used herein refer to an isoform of PCNA having an acidic isoelectric point (e.g., peptide including protonated amine and / or carboxyl groups, acidic isoelectric point compared to a non-cancer-associated PCNA, PCNA in non-cancerous cells, non-malignant PCNA, prevalent PCNA isoform in non-cancerous cells, or less acidic PCNA isoform in non- cancerous cells). In embodiments, the caPCNA protein includes methylated amino acids (e.g., glutamate, aspartic acid). In embodiments, the caPCNA protein is post-translationally modified with a methylester of an acidic amino acid. In embodiments, the methylesterification of the acidic amino acid residues on PCNA exhibit a T1 / 2of approximately 20 minutes at pH 8.5. In embodiments, caPCNA is post-translationally modified as described in F. Shen, et al. J Cell Biochem.2011 Mar; 112(3): 756–760, which is incorporated by reference in its entirety for all purposes.

[0056] The terms “non-malignant Proliferating cell nuclear antigen” or “nmPCNA” as used herein refer to an isoform of PCNA having a basic isoelectric point (e.g., peptide including deprotonated amine and / or carboxyl groups, basic isoelectric point compared to a caPCNA, caPCNA in cancerous cells). In embodiments, nmPCNA is the prevalent PCNA isoform in non-cancerous cells.

[0057] The term “spray-dried dispersion” or “SDD” is used in accordance with its plain ordinary meaning in the art and refers to a technique that turns a mixture of a drug and a polymer into a powder that can improve the drug’s solubility and bioavailability. In embodiments, the spray-dried dispersion is as described in Newman, A. (Ed.), 2015,Pharmaceutical Amorphous Solid Dispersions, Wiley, ISBN: 978-1-118-90141-0; Qiu, Y., Chen, Y., Zhang, G., Yu, L., Mantri, R. V. (Eds.), 2016, Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice, 2nd edition, Elsevier, Hardcover ISBN: 9780128024478, Ebook ISBN: 9780128026373; or Khutoryanskiy, V., Al-Obaidi, H. (Eds.), 2022, Solid Dispersions for Drug Delivery: Applications and Preparation Methods, Springer Nature, ISBN: 9783036526393; which are hereby incorporated by reference in their entirety for all purposes. II. Pharmaceutical compositions

[0058] In an aspect is provided a pharmaceutical composition including a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof.(I) is also referred to herein as AOH1996.

[0060] In embodiments, the pharmaceutically acceptable excipient is hydroxypropyl methylcellulose. In embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose acetate succinate, medium grade granule (HPMC AS-MG).

[0061] In embodiments, the therapeutically effective amount of the compound is 150 mg. In embodiments, the ratio of the compound to HPMC AS-MG is 1:4. In embodiments, the pharmaceutical composition includes a 20% drug load of the compound.

[0062] In embodiments, the therapeutically effective amount of the compound is the amount of the compound in a single tablet. In embodiments, the amount of the compound in a single tablet is from about 100 mg to about 200 mg. In embodiments, the amount of the compound in a single tablet is about 100 mg. In embodiments, the amount of the compound in a single tablet is about 110 mg. In embodiments, the amount of the compound in a single tablet is about 120 mg. In embodiments, the amount of the compound in a single tablet is about 130 mg. In embodiments, the amount of the compound in a single tablet is about 140 mg. In embodiments, the amount of the compound in a single tablet is about 150 mg. Inembodiments, the amount of the compound in a single tablet is about 160 mg. In embodiments, the amount of the compound in a single tablet is about 170 mg. In embodiments, the amount of the compound in a single tablet is about 180 mg. In embodiments, the amount of the compound in a single tablet is about 190 mg. In embodiments, the amount of the compound in a single tablet is about 200 mg.

[0063] In embodiments, the amount of the compound in a single tablet is from 100 mg to 200 mg. In embodiments, the amount of the compound in a single tablet is 100 mg. In embodiments, the amount of the compound in a single tablet is 110 mg. In embodiments, the amount of the compound in a single tablet is 120 mg. In embodiments, the amount of the compound in a single tablet is 130 mg. In embodiments, the amount of the compound in a single tablet is 140 mg. In embodiments, the amount of the compound in a single tablet is 150 mg. In embodiments, the amount of the compound in a single tablet is 160 mg. In embodiments, the amount of the compound in a single tablet is 170 mg. In embodiments, the amount of the compound in a single tablet is 180 mg. In embodiments, the amount of the compound in a single tablet is 190 mg. In embodiments, the amount of the compound in a single tablet is 200 mg.

[0064] In embodiments, the compound is in a non-crystalline state with the hydroxypropyl methylcellulose.

[0065] In embodiments, the pharmaceutical composition further includes a direct compression excipient, a sweetener, a disintegrant, a stabilizer, a thickening agent, and a tableting agent.

[0066] In embodiments, the pharmaceutical composition further includes a direct compression excipient. In embodiments, the direct compression excipient is microcrystalline cellulose. In embodiments, the direct compression excipient is microcrystalline cellulose PH- 102. In embodiments, the microcrystalline cellulose has the CAS number 9004-34-6.

[0067] In embodiments, the pharmaceutical composition further includes a sweetener. In embodiments, the sweetener is mannitol, xylitol, aspartame, or sucralose. In embodiments, the sweetener is mannitol. In embodiments, the sweetener is D-mannitol. In embodiments, the sweetener is mannitol 100SD, wherein the average mean particle diameter is 100 µm.

[0068] In embodiments, the pharmaceutical composition further includes a disintegrant. In embodiments, the disintegrant is carmellose (carboxymethyl cellulose), carmellose calcium,carmellose sodium, hydroxypropylcellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crystalline cellulose, carboxymethyl starch sodium, crospopidone, corn starch, or talc. In embodiments, the disintegrant is croscarmellose sodium. In embodiments, the disintegrant is croscarmellose sodium SD-711.

[0069] In embodiments, the pharmaceutical composition further includes a stabilizer. In embodiments, the stabilizer is colloidal silicon dioxide. In embodiments, the colloidal silicon dioxide has the CAS number 112945-52-5. In embodiments, the colloidal silicon dioxide has the CAS number 7631-86-9.

[0070] In embodiments, the pharmaceutical composition further includes a thickening agent. In embodiments, the thickening agent is hydroxypropyl cellulose.

[0071] In embodiments, the pharmaceutical composition further includes a tableting agent. In embodiments, the tableting agent is magnesium stearate. In embodiments, the magnesium stearate has the CAS number 557-04-0.

[0072] In embodiments, the pharmaceutical composition further includes a film coating system. In embodiments, the film coating system is film coating system 88A130067-CN Orange. In embodiments, film coating system 88A130067-CN Orange comprises polyvinyl alcohol, talc, titanium dioxide, glyceryl mono and dicaprylocaprate, sodium lauryl sulfate, yellow iron oxide non-IRR, and red iron oxide non-IRR.

[0073] In embodiments, the pharmaceutical composition includes from about 60% to about 65% by weight of the compound in a non-crystalline state with the hydroxypropyl methylcellulose, from about 12% to about 15% by weight of microcrystalline cellulose, from about 12% to about 15% by weight of mannitol, from about 4% to about 6% by weight of croscarmellose sodium, from about 4% to about 6% by weight of colloidal silicon dioxide, from about 2% to about 4% by weight of hydroxypropyl cellulose, from about 1% to about 2% by weight of magnesium stearate, and from about 2% to about 4% by weight of film coating system.

[0074] In embodiments, the pharmaceutical composition includes 62.5% by weight of the compound in a non-crystalline state with the hydroxypropyl methylcellulose, 13.5% by weight of microcrystalline cellulose, 13.5% by weight of mannitol, 5% by weight of croscarmellose sodium, 1% by weight of colloidal silicon dioxide, 3% by weight ofhydroxypropyl cellulose, 1.5% by weight of magnesium stearate, and 3% by weight of film coating system.

[0075] In embodiments, the pharmaceutical composition includes 62.5% by weight of the compound in a non-crystalline state with the hydroxypropyl methylcellulose, 13.5% by weight of microcrystalline cellulose, 13.5% by weight of mannitol, 5% by weight of croscarmellose sodium, 1% by weight of colloidal silicon dioxide, 3% by weight of hydroxypropyl cellulose, and 1.5% by weight of magnesium stearate.

[0076] In embodiments, the pharmaceutical composition includes 150 mg of the compound, 600 mg of HPMC AS-MG, 162 mg of microcrystalline cellulose, 162 mg of mannitol, 60 mg of croscarmellose sodium, 12 mg of colloidal silicon dioxide, 36 mg of hydroxypropyl cellulose, 18 mg of magnesium stearate, and 36 mg of film coating system.

[0077] In embodiments, the pharmaceutical composition includes 150 mg of the compound, 600 mg of HPMC AS-MG, 162 mg of microcrystalline cellulose, 162 mg of mannitol, 60 mg of croscarmellose sodium, 12 mg of colloidal silicon dioxide, 36 mg of hydroxypropyl cellulose, and 18 mg of magnesium stearate.

[0078] In an aspect is provided a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof; wherein the150 mg; and wherein the pharmaceutical composition is in a tablet form suitable for human oral administration.

[0079] In embodiments, the dimensions of the tablet are from about 19 mm to about 23 mm in length, from about 8 mm to about 12 mm in width, and from about 5 mm to about 9 mm in height. In embodiments, the dimensions of the tablet are about 21 mm in length, about 10 mm in width, and about 7 mm in height. In embodiments, the dimensions of the tablet are 20.92 mm in length, 9.91 mm in width, and 7.2 mm in height.

[0080] In embodiments, the pharmaceutically acceptable excipient is hydroxypropyl methylcellulose acetate succinate, medium grade granule (HPMC AS-MG).

[0081] In embodiments, the pharmaceutical composition is in a spray-dried dispersion- based tablet form. III. Methods of use

[0082] In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject the pharmaceutical composition described herein, including in embodiments.

[0083] In embodiments, the pharmaceutical composition is administered twice daily. In embodiments, 6 to 15 tablets of the pharmaceutical composition are administered twice daily.

[0084] In embodiments, 6 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 1,800 mg. In embodiments, 7 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,100 mg. In embodiments, 8 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,400 mg. In embodiments, 9 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,700 mg. In embodiments, 10 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,000 mg. In embodiments, 11 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,300 mg. In embodiments, 12 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,600 mg. In embodiments, 13 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,900 mg. In embodiments, 14 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 4,200 mg. In embodiments, 15 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 4,500 mg.

[0085] In embodiments, the total therapeutically effective amount of the compound administered daily is 1,800 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 2,100 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 2,400 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 2,700 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 3,000 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 3,300 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 3,600 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 3,900 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 4,200 mg. In embodiments, the total therapeutically effective amount of the compound administered daily is 4,500 mg.

[0086] In embodiments, 6 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 7 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 8 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 9 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 10 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 11 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 12 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 13 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 14 tablets of the pharmaceutical composition are administered twice daily. In embodiments, 15 tablets of the pharmaceutical composition are administered twice daily.

[0087] In embodiments, the cancer is a solid tumor. In embodiments, the cancer is a sarcoma, adenocarcinoma, leukemia, or lymphoma. In embodiments, the cancer is a lung cancer, colon cancer, central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, mesothelioma, liver cancer, stomach cancer, esophageal cancer, bladder cancer, cervical cancer, osteosarcoma, pancreatic cancer, adrenal cortical cancer, adrenal gland cancer, colorectal cancer, testicular cancer, myeloma, B-acute lymphoblastic lymphoma, non- Hodgkin’s lymphoma, Hodgkin’s lymphoma, chronic leukemia, acute leukemia, glandularcarcinoma, or hematoid carcinoma. In embodiments, the cancer is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, eosinophilic leukemia, lymphoblastic leukemia, acute myeloid leukemia, squamous cell carcinoma, adenocarcinoma, glioblastoma, astrocytoma, superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral- lentiginous melanoma, endometrial cancer, mucinous carcinoma, papillary carcinoma, papillary thyroid cancer, medullary thyroid cancer, basal cell carcinoma, hepatocellular carcinoma, cholangiocellular carcinoma, gastric cancer, transitional cell carcinoma, B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, or Hodgkin’s lymphoma. In embodiments, the cancer is a sarcoma. In embodiments, the cancer is adenocarcinoma. In embodiments, the cancer is leukemia. In embodiments, the cancer is lymphoma. In embodiments, the cancer is a CNS cancer. In embodiments, the cancer is melanoma. In embodiments, the cancer is renal cancer. In embodiments, the cancer is metastatic cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is triple negative breast cancer. In embodiments, the cancer is metastatic breast cancer. In embodiments, the cancer is brain cancer. In embodiments, the cancer is neuroblastoma. In embodiments, the cancer is glioblastoma. In embodiments, the cancer is astrocytoma. In embodiments, the cancer is glioma. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is acute myeloid leukemia (AML). In embodiments, the cancer is chronic lymphoid leukemia (CLL). In embodiments, the cancer is non-Hodgkin’s lymphoma. In embodiments, the cancer is skin cancer. In embodiments, the cancer is squamous cell carcinoma. In embodiments, the cancer is T lymphotrophic leukemia. In embodiments, the cancer is malignant melanoma. In embodiments, the cancer is lung cancer. In embodiments, the cancer is non-small cell lung cancer. In embodiments, the cancer is small-cell lung cancer. In embodiments, the cancer is colon cancer. In embodiments, the cancer is prostate cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is kidney cancer. In embodiments, the cancer is osteosarcoma. In embodiments, the cancer may be prostate, thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples may include, but are not limited to Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, neuroblstoma, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary braintumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer,papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. In embodiments, thecancer is leukemia, myeloma, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer. In embodiments, the cancer is triple negative breast cancer. In embodiments, the cancer is a central nervous system (CNS) cancer. In embodiments, the cancer is a sympathetic nervous system (SNS) cancer. In embodiments, the cancer is an adrenal gland cancer. In embodiments, the cancer is a cancer of a neuron in the neck, chest, abdomen, or pelvis. In embodiments, the cancer is an esthesioneuroblastoma. In embodiments, the cancer is a stage 1 neuroblastoma (e.g., localized tumor confined to an area near the origin). In embodiments, the cancer is a a stage 2A neuroblastoma (e.g., Unilateral tumor with incomplete gross resection and / or identifiable ipsilateral and contralateral lymph node negative for tumor). In embodiments, the cancer is a a stage 2B neuroblastoma (e.g., Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor). In embodiments, the cancer is a a stage 3 neuroblastoma (e.g., Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement). In embodiments, the cancer is a a stage 4 neuroblastoma (e.g., Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S). In embodiments, the cancer is a a stage 4S neuroblastoma (e.g., Age <1 year old with localized primary tumor as described in Stage 1 or Stage 2 above, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors). In embodiments, the cancer is a stage L1 neuroblastoma (e.g., localized cancer without image-defined risk factors) according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the cancer is a stage L2 neuroblastoma (e.g., localized cancer with image-defined risk factors) according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the cancer is a stage M neuroblastoma (e.g., metastatic cancer) according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, thecancer is a stage MS neuroblastoma (e.g., metastatic cancer "special" where MS is equivalent to stage 4S as described above) according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the cancer is a neuroblastoma risk stratification pre-treatment group, according to the International Neuroblastoma Risk Group (INRG) staging system, of very low. In embodiments, the cancer is a neuroblastoma risk stratification pre-treatment group, according to the International Neuroblastoma Risk Group (INRG) staging system, of low. In embodiments, the cancer is a neuroblastoma risk stratification pre-treatment group, according to the International Neuroblastoma Risk Group (INRG) staging system, of intermediate. In embodiments, the cancer is a neuroblastoma risk stratification pre-treatment group, according to the International Neuroblastoma Risk Group (INRG) staging system, of high risk.

[0088] In embodiments, the cancer is cervical cancer, colon cancer, thyroid cancer, gastric cancer, ovarian cancer, breast cancer, lung cancer, uterine cancer, or Ductal carcinoma in situ (DCIS). In embodiments, the cancer is cervical cancer. In embodiments, the cancer is colon cancer. In embodiments, the cancer is thyroid cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is lung cancer. In embodiments, the cancer is uterine cancer. In embodiments, the cancer is Ductal carcinoma in situ (DCIS).

[0089] In embodiments, the cancer is esophageal adenocarcinoma. In embodiments, the cancer is stage 0 esophageal cancer. In embodiments, the cancer is stage I esophageal cancer. In embodiments, the cancer is stage IA esophageal cancer. In embodiments, the cancer is stage IB esophageal cancer. In embodiments, the cancer is stage IIA esophageal cancer. In embodiments, the cancer is stage IIB esophageal cancer. In embodiments, the cancer is stage IIIA esophageal cancer. In embodiments, the cancer is stage IIIB esophageal cancer. In embodiments, the cancer is stage IIIC esophageal cancer. In embodiments, the cancer is stage IV esophageal cancer. In embodiments, the cancer is stage I esophageal adenocarcinoma. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is prostate cancer (e.g., prostatic adenocarcinoma). In embodiments, the cancer is high-grade prostatic intraepithelial neoplasia (PIN). In embodiments, the cancer is associated with Barrett’s esophagus. In embodiments, the cancer is associated with Barrett’s esophagus without epithelial dysplasia. In embodiments, the cancer is associated with Barrett’s esophagus with low grade epithelial dysplasia. In embodiments, the cancer is associated withBarrett’s esophagus with high-grade epithelial dysplasia. In embodiments, the cancer is oesophagogastric junctional adenocarcinoma. In embodiments, the cancer is described in Hammoud et al. (Z. T. Hammoud, et al. Journal of Thoracic & Cardiovascular Surgery 2006;133(1):82-87); Wang X., et al. Prostate.2011 May 15;71(7):748-54; or Shen F., et al. J Cell Biochem.2011 Mar;112(3):756-60, which are incorporated by reference in their entirety for all purposes. IV. Methods of making

[0090] In an aspect is provided a method of making the pharmaceutical composition described herein, the method including spray-drying. In embodiments, the spray-drying method includes: (i) adding a solvent to a reaction vessel;(ii) adding the compound of formula (I) to the reaction vessel and stirring until thecompound is dissolved; (iii) adding the hydroxypropyl methylcellulose to the reaction vessel and stirring untilthe mixture is free of particulates; (iv) filtering the mixture, thereby forming a filtered mixture;(v) spray-drying the filtered mixture, thereby forming a spray-dried dispersion; and(vi) drying the spray-dried dispersion.

[0091] In embodiments, the solvent is acetone.

[0092] In embodiments, in step (ii), the compound of formula (I) is added slowly under continuous stirring at 150 ± 50 rpm at room temperature for at least 15 minutes.

[0093] In embodiments, in step (iii), the mixture is stirred at 150 ± 50 rpm for at least two hours.

[0094] In embodiments, in step (iv), the mixture is filtered through a 50 µm filter.

[0095] In embodiments, step (vi) includes adding the spray-dried dispersion to a vacuum tray dryer and drying at a temperature of from about 40 °C to about 55 °C, preferably about 45 °C. In embodiments, every two hours, the spray-dried dispersion is raked and lumps are removed. In embodiments, residual acetone should be less than about 450 ppm.

[0096] In embodiments, the method further includes pre-blending, roller compaction, blending / lubrication, tablet compression, coating, bottling, and labelling.

[0097] In embodiments, the pre-blending step includes mixing microcrystalline cellulose and colloidal silicon dioxide, and passing the mixture through a milling machine, thereby forming a milled material. In embodiments, the milling machine is a Comil. In embodiments, the pre-blending step further includes adding the milled material, the spray- dried dispersion of AOH1996: hydroxypropyl methylcellulose, and croscarmellose sodium and mannitol to a bin, thereby forming a pre-blended product.

[0098] In embodiments, the roller compaction step includes applying pressure to the pre- blended product, thereby forming a ribbon. In embodiments, the pressure is 4 MPa. In embodiments, the ribbon is passed through a granulation screen, thereby forming granules. V. Embodiments

[0099] Embodiment P1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof; wherein theis hydroxypropyl methylcellulose.

[0100] Embodiment P2. The pharmaceutical composition of embodiment P1, wherein the therapeutically effective amount of the compound is 150 mg.

[0101] Embodiment P3. The pharmaceutical composition of embodiments P1 or P2, wherein the compound is in a non-crystalline state with the hydroxypropyl methylcellulose.

[0102] Embodiment P4. The pharmaceutical composition of one of embodiments P1 to P3, wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose acetate succinate, medium grade granule (HPMC AS-MG).

[0103] Embodiment P5. The pharmaceutical composition of one of embodiments P1 to P4, further comprising a sweetener, a disintegrant, a stabilizer, a thickening agent, and a tableting agent.

[0104] Embodiment P6. The pharmaceutical composition of embodiment P5, wherein the sweetener is mannitol.

[0105] Embodiment P7. The pharmaceutical composition of embodiment P5, wherein the disintegrant is croscarmellose sodium.

[0106] Embodiment P8. The pharmaceutical composition of embodiment P5, wherein the stabilizer is colloidal silicon dioxide.

[0107] Embodiment P9. The pharmaceutical composition of embodiment P5, wherein the thickening agent is hydroxypropyl cellulose.

[0108] Embodiment P10. The pharmaceutical composition of embodiment P5, wherein the tableting agent is magnesium stearate.

[0109] Embodiment P11. The pharmaceutical composition of embodiment P1, comprising 62.5% by weight of the compound in a non-crystalline state with the hydroxypropyl methylcellulose, 13.5% by weight of microcrystalline cellulose, 13.5% by weight of mannitol, 5% by weight of croscarmellose sodium, 1% by weight of colloidal silicon dioxide, 3% by weight of hydroxypropyl cellulose, and 1.5% by weight of magnesium stearate.

[0110] Embodiment P12. The pharmaceutical composition of one of embodiments P1 to P11, wherein the pharmaceutical composition is in a spray-dried dispersion-based tablet form.

[0111] Embodiment P13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof; wherein the150 mg; and wherein the pharmaceutical composition is in a tablet form suitable for human oral administration.

[0112] Embodiment P14. The pharmaceutical composition of embodiment P12, wherein the dimensions of the tablet are about 21 mm in length, about 10 mm in width, and about 7 mm in height.

[0113] Embodiment P15. The pharmaceutical composition of embodiment P12, wherein the dimensions of the tablet are 20.92 mm in length, 9.91 mm in width, and 7.2 mm in height.

[0114] Embodiment P16. The pharmaceutical composition of one of embodiments P12 to P15, wherein the pharmaceutically acceptable excipient is hydroxypropyl methylcellulose acetate succinate, medium grade granule (HPMC AS-MG).

[0115] Embodiment P17. The pharmaceutical composition of one of embodiments P13 to P16, wherein the pharmaceutical composition is in a spray-dried dispersion-based tablet form.

[0116] Embodiment P18. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject the pharmaceutical composition of one of embodiments P1 to P17.

[0117] Embodiment P19. The method of embodiment P18, wherein the pharmaceutical composition is administered twice daily.

[0118] Embodiment P20. The method of embodiment P19, wherein 6 to 15 tablets of the pharmaceutical composition are administered twice daily.

[0119] Embodiment P21. The method of embodiment P20, wherein 6 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 1,800 mg.

[0120] Embodiment P22. The method of embodiment P20, wherein 7 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,100 mg.

[0121] Embodiment P23. The method of embodiment P20, wherein 8 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,400 mg.

[0122] Embodiment P24. The method of embodiment P20, wherein 9 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,700 mg.

[0123] Embodiment P25. The method of embodiment P20, wherein 10 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,000 mg.

[0124] Embodiment P26. The method of embodiment P20, wherein 11 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,300 mg.

[0125] Embodiment P27. The method of embodiment P20, wherein 12 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,600 mg.

[0126] Embodiment P28. The method of embodiment P20, wherein 13 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,900 mg.

[0127] Embodiment P29. The method of embodiment P20, wherein 14 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 4,200 mg.

[0128] Embodiment P30. The method of embodiment P20, wherein 15 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 4,500 mg.

[0129] Embodiment P31. The method of one of embodiments P18 to P30, wherein said cancer is a solid tumor.

[0130] Embodiment P32. The method of one of embodiments P18 to P30, wherein said cancer is a lung cancer, colon cancer, central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, mesothelioma, liver cancer, stomach cancer, esophageal cancer, bladder cancer, cervical cancer, osteosarcoma, pancreatic cancer, adrenal cortical cancer, adrenal gland cancer, colorectal cancer, testicular cancer, myeloma, B-acutelymphoblastic lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, chronic leukemia, acute leukemia, glandular carcinoma, or hematoid carcinoma.

[0131] Embodiment P33. The method of one of embodiments P18 to P30, wherein said cancer is acute myeloid leukemia, pancreatic cancer, or osteosarcoma. VI. Additional embodiments

[0132] Embodiment 1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof; wherein the is hydroxypropyl methylcellulose.

[0133] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of the compound is 150 mg.

[0134] Embodiment 3. The pharmaceutical composition of embodiment 1 or 2, wherein the compound is in a non-crystalline state with the hydroxypropyl methylcellulose.

[0135] Embodiment 4. The pharmaceutical composition of any one of embodiments 1 to 3, wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose acetate succinate, medium grade granule (HPMC AS-MG).

[0136] Embodiment 5. The pharmaceutical composition of any one of embodiments 1 to 4, further comprising a sweetener, a disintegrant, a stabilizer, a thickening agent, and a tableting agent.

[0137] Embodiment 6. The pharmaceutical composition of embodiment 5, wherein the sweetener is mannitol.

[0138] Embodiment 7. The pharmaceutical composition of embodiment 5, wherein the disintegrant is croscarmellose sodium.

[0139] Embodiment 8. The pharmaceutical composition of embodiment 5, wherein the stabilizer is colloidal silicon dioxide.

[0140] Embodiment 9. The pharmaceutical composition of embodiment 5, wherein the thickening agent is hydroxypropyl cellulose.

[0141] Embodiment 10. The pharmaceutical composition of embodiment 5, wherein the tableting agent is magnesium stearate.

[0142] Embodiment 11. The pharmaceutical composition of embodiment 1, comprising 62.5% by weight of the compound in a non-crystalline state with the hydroxypropyl methylcellulose, 13.5% by weight of microcrystalline cellulose, 13.5% by weight of mannitol, 5% by weight of croscarmellose sodium, 1% by weight of colloidal silicon dioxide, 3% by weight of hydroxypropyl cellulose, and 1.5% by weight of magnesium stearate.

[0143] Embodiment 12. The pharmaceutical composition of any one of embodiments 1 to 11, wherein the pharmaceutical composition is in a spray-dried dispersion-based tablet form.

[0144] Embodiment 13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof; wherein the150 mg; and wherein the pharmaceutical composition is in a tablet form suitable for human oral administration.

[0145] Embodiment 14. The pharmaceutical composition of embodiment 13, wherein the dimensions of the tablet are about 21 mm in length, about 10 mm in width, and about 7 mm in height.

[0146] Embodiment 15. The pharmaceutical composition of embodiment 13, wherein the dimensions of the tablet are 20.92 mm in length, 9.91 mm in width, and 7.2 mm in height.

[0147] Embodiment 16. The pharmaceutical composition of any one of embodiments 13 to 15, wherein the pharmaceutically acceptable excipient is hydroxypropyl methylcellulose acetate succinate, medium grade granule (HPMC AS-MG).

[0148] Embodiment 17. The pharmaceutical composition of any one of embodiments 13 to 16, wherein the pharmaceutical composition is in a spray-dried dispersion-based tablet form.

[0149] Embodiment 18. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject the pharmaceutical composition of any one of embodiments 1 to 17.

[0150] Embodiment 19. The method of embodiment 18, wherein the pharmaceutical composition is administered twice daily.

[0151] Embodiment 20. The method of embodiment 19, wherein 6 to 15 tablets of the pharmaceutical composition are administered twice daily.

[0152] Embodiment 21. The method of embodiment 20, wherein 6 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 1,800 mg.

[0153] Embodiment 22. The method of embodiment 20, wherein 7 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,100 mg.

[0154] Embodiment 23. The method of embodiment 20, wherein 8 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,400 mg.

[0155] Embodiment 24. The method of embodiment 20, wherein 9 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,700 mg.

[0156] Embodiment 25. The method of embodiment 20, wherein 10 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,000 mg.

[0157] Embodiment 26. The method of embodiment 20, wherein 11 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,300 mg.

[0158] Embodiment 27. The method of embodiment 20, wherein 12 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,600 mg.

[0159] Embodiment 28. The method of embodiment 20, wherein 13 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,900 mg.

[0160] Embodiment 29. The method of embodiment 20, wherein 14 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 4,200 mg.

[0161] Embodiment 30. The method of embodiment 20, wherein 15 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 4,500 mg.

[0162] Embodiment 31. The method of any one of embodiments 18 to 30, wherein said cancer is a solid tumor.

[0163] Embodiment 32. The method of any one of embodiments 18 to 30, wherein said cancer is a lung cancer, colon cancer, central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, mesothelioma, liver cancer, stomach cancer, esophageal cancer, bladder cancer, cervical cancer, osteosarcoma, pancreatic cancer, adrenal cortical cancer, adrenal gland cancer, colorectal cancer, testicular cancer, myeloma, B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, chronic leukemia, acute leukemia, glandular carcinoma, or hematoid carcinoma.

[0164] Embodiment 33. The method of any one of embodiments 18 to 30, wherein said cancer is acute myeloid leukemia, pancreatic cancer, or osteosarcoma.

[0165] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview ofthis application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. EXAMPLES Example 1: Formulation development

[0166] Three formulation methods – nano-suspension, lipid-based emulsion, and spray dried dispersion (SDD) – of AOH1996 were developed and tested. The objective of the study was to develop an adult formulation for oral delivery of AOH1996 (API). Multiple formulation prototypes were designed and screened for each formulation approach. Based on the highest achievable drug load (DL) and stability of the prototypes, the 20% DL SDD formulation was chosen for GMP development.

[0167] 1. Nano-suspension

[0168] A nano-suspension generally refers to a submicron colloidal dispersion of pure drug particles, stabilized by surfactants. It may be used to improve the solubility, bioavailability, and delivery of poorly soluble drugs. The drug particles may be reduced to the nanometer range (generally less than 1 micron), which results in an increased surface area and therefore improved dissolution rate.

[0169] Advantages may include: ^Improved solubility and bioavailability^ Enhanced drug stability^ Dose reduction^ Controlled release^ Suitability for poorly water-soluble drugs

[0170] The crystalline form, initial particle size, and purity of AOH1996 (API) was characterized. The concentration of API at 100 mg / mL was wet milled in 4 prototypes (PT1- 4) to reduce the API particle size to approximately 200 nm (Table 1). The physical and chemical stability of the prototypes were evaluated under 25oC as measured by the changes in particle size distribution (PSD) and purity. Pt2 and Pt4 were stable as determined by the change in PSD within the rage of 50-100 mm and purity decrease less than 0.2% for one week. The API pharmacokinetics (PK) in both prototypes was tested in dogs and was not asfavorable as the PK of the previous Softgel formulation (Table 2). As a result, the non- suspension approach was not pursued further for GMP development.

[0171] Table 1. Nano-suspension prototypes Prototype No. Vehicle (w / v, %)Pt 1 0.5% HPMC E5 / 0.5% Tween80

[0172] Table 2. Softgel formulation summary Fill formulation: Material Function w / w (%) Unit formula (mg) r )

[0173] 2. Lipid-based emulsion

[0174] A lipid emulsion generally refers to a mixture of lipids (fats or oils) and water, stabilized by an emulsifying agent. Lipid emulsions are delivery systems that may be used to enhance the bioavailability of poorly water-soluble drugs. These formulations may use lipids (fats or oils), which can improve the solubility of these drugs and facilitate their absorption in the gastrointestinal tract.

[0175] Advantages may include: ^Improved bioavailability^ Lymphatic delivery^ Reduced food effect^ Protection of labile drugs^ Controlled and targeted drug delivery^ Suitable for liquid and solid dosage forms

[0176] API solubility was tested in a broad panel of different functional excipients. It was discovered that the API showed good solubility in Capmul MCM, Kolliphor, RH40, Cremophor EL, Solutol HS15 Transcutol, and PEG 400 (Table 3).

[0177] Table 3. API solubility Functionality Vehicle Appro 25 oximate Solubility (mg / omL) C50 C

[0178] Based on the solubility results, a total of 9 prototypes were designed and screened for stability (Table 4). Prototypes were diluted in simulated gastric fluid (SGF) and fasted state simulated intestinal fluid (FaSSIF) to screen out potential API precipitation in vivo. While Prototypes 1-5 turned opaque after fluid challenge indicating precipitation, Prototypes 6-9 remained clear. However, further increase in the drug load in these prototypes above 40 mg / mL was not achieved.

[0179] Table 4. Lipid-based emulsion prototypes Formula Target conc. No. (mg / mL) Formula composition (v / v%) Observation nnn nn

[0180] 3. Spray dried dispersion (SDD)

[0181] Amorphous Solid Dispersion (ASD) generally refers to a strategy used to improve the solubility and bioavailability of poorly soluble drugs. In an ASD, the drug may be dispersed within a polymer matrix in an amorphous (non-crystalline) state. This state can increase the dissolution rate and solubility of the drug because amorphous substances have higher free energy and are more soluble than their crystalline counterparts. However, amorphous forms may be thermodynamically unstable and may convert back to their crystalline form during storage or processing. Therefore, the identification of suitable polymers and proper formulation techniques are important to achieve and maintain formulation stability.

[0182] In embodiments, the process of spray-drying may generally include: 1. Atomization. The solution may be pumped through a nozzle, where it is atomizedinto fine droplets. This action may be facilitated by nitrogen gas (N2) which helps to break the liquid stream into a spray of tiny, uniform droplets. 2. Initial contact with hot gas. As the droplets are formed, they may be immediatelyexposed to a stream of hot nitrogen gas within the spray dryer chamber. The largesurface area of the droplets facilitates rapid heat transfer from the hot gas to the droplets. 3. Evaporation. The heat from the nitrogen gas may cause the solvent, usually water oran organic solvent, within the droplets to evaporate quickly. This phase change from liquid to vapor removes energy from the droplet, cooling the gas slightly but significantly reducing the droplet's size. 4. Particle formation. As the solvent evaporates, the solutes or solid materials within thedroplet may become concentrated. Once the solvent is completely evaporated, what remains is a dry particle. 5. Final SDD particle. The completely dried particles achieve a solid state, which maybe referred to as Spray Dried Dispersion (SDD) particles.

[0183] Advantages may include: ^Improved solubility and bioavailability^ Enhanced dissolution rate^ Physical stability^ Flexible formulation options^ Controlled release

[0184] To develop amorphous solid dispersion (ASD) of AOH1196, API / polymer mixture with a target DL of 20% was evaluated. Based on kinetic solubility in FaSSIF and physical characterization for polymer screening, HPMC ASLG, HPMC ASMG and Eudragit EPO were identified as candidate polymers to generate homogeneous solid dispersion (see Example 2 for further details). Further kinetic solubility tests resulted in the identification of HPMC AS-MG and Eudragit EPO for further testing and development.

[0185] Dissolution and stability studies were conducted on DL of 20%-50% with HPMC AS-MG as the excipient. A drug load of 20% was selected since API recrystallization was observed under higher DLs. Animal studies showed ASD formulation produced a similar PK compared to Softgel. In addition, the 20% DL is much higher than that of the Softgel formulation (4%). Therefore, the ASD was chosen to move forward for GMP development.Example 2: ASD development

[0186] Part 1

[0187] ASD development: API had low solubility and low bioavailability in animal study. To gain sufficient drug exposure, a large dosage size is required under the previous lipid- based formulation, which led to a poor patient compliance. Amorphous solid dispersion (ASD) is a formulation technique that may be used to improve the solubility and bioavailability of drugs. It involves the dispersion of a crystalline drug in an amorphous (non-crystalline) matrix using polymer excipients and is particularly useful for drugs that are poorly soluble in water. It can help increase their dissolution rate and improve their absorption in the body.

[0188] 1. Identification of ASD polymer excipient:

[0189] AOH1996 stays amorphous in the presence of a broad range of polymer excipients in 20%DL API / polymer mixture prepared by the by fast evaporation method. To evaluate in- vitro release performance, kinetic solubility was performed in FaSSIF to determine how the compound dissolve and potentially be absorbed in fluid from the upper intestine. As shown in Table 5, solid dispersion of several polymers showed solubility enhancement than pure API in bio-media. HPMC ASLG, HPMC ASMG and Eudragit EPO had highest solubility improvement and were selected for further development.

[0190] Table 5. Kinetic solubility of ASD in FaSSIF No. SD AppearanceKinetic solubility (μg / mL)Final5 1 6 0 5 6 1 2 29 Eudragit EPO Suspension 451.12 787.40 1210.42 1738.87 7.1010 Eudragit Sus ension 3077 1475 1235 1876 593

[0191] 2. ASD preparation by spray drying:

[0192] API / polymer mixture were prepared for HPMC ASLG, HPMC ASMG and Eudragit EPO by spray drying to select the optimal polymer at 20%DL. It was determined by XRPD that all three ASD were amorphous. ASD with HPMC ASMG appeared to be the stable as indicated by its high glass transition temperature of Tg = 109oC (measured by mDSC). A 2- step dissolution in study in the presence of SGF and FaSSIF revealed that ASD with HPMC ASMG enhanced API dissolution the most (Table 6).

[0193] Table 6. Kinetic solubility of ASD in SGF and FaSSIF 2-step kinetic solubility (μg / mL) e e e e

[0194] 3. ASD stability

[0195] Stability of ASD with HPMC ASMG at 20%DL. ASD was evaluated at conditions of 25°C / 60%RH and 40°C / 75%RH by XRPD and HPLC. ASD with HPMC ASMG was physically and chemically stable at both 25°C / 60%RH and 40°C / 75%RH conditions for at least 6 months.

[0196] Based on ASD dissolution and stability, ASD with HPMC ASMG at 20%DL was selected as the lead formulation for further development.

[0197] Part 2

[0198] ASD drug loading optimization

[0199] Based on the successful preparation of 20% DL ASD, the ASD drug using the same excipient (HPMC ASMG) but increased DL (30%, 40% and 50%) were tested.

[0200] A two-step dissolution in the presence of SGF and FaSSIF revealed that ASD of all 3 DLs enhanced compound dissolution in comparison with the crystalline API (>10 times) (FIG.1). Dissolution decreased as DL increased (concentration at 120 min: API=1 μg / mL; 30%DL=26 μg / mL; 40%DL=19 μg / mL; 50%=10 μg / mL). Recrystallization was observed for 50%DL.

[0201] The stability of ASD with different DLs were investigated under 25°C / 60%RH and 40°C / 75%RH for 2 weeks. As shown in Table 7, ASD of all 3 DLs were physically and chemically stable at 25ºC / 60%RH for two weeks. None had chemical purity change at 40ºC / 75%RH for 2 weeks. 40%DL & 50%DL ASD had appearance change and recrystallization at 40ºC / 75%RH. SEM examination also indicated the potential crystallization risk of the 30% DL ASD.

[0202] Table 7. Stability results at 25 ºC / 60%RH and 40 ºC / 75%RH of ASDs 25ºC / 60%RH Time 1 week 2 weeks mmnn

[0203] Given that higher DL ASD recrystallizes or has risk to recrystallize, the 20% DL ASD was selected for GMP development.

[0204] ASD composition: ASD 20%DL: 20% API+ 80% HPMC ASMGASD 30%DL: 30% API+ 70% HPMC ASMG ASD 40%DL: 40% API+ 60% HPMC ASMG ASD 50%DL: 50% API+ 50% HPMC ASMG

[0205] Abbreviations HPMC ASMG: Hydroxypropyl Methylcellulose Acetate Succinate MG HPMC ASLG: Hydroxypropyl Methylcellulose Acetate Succinate LG Example 3: Spray-dried dispersion of AOH1996

[0206] Based on our tests, 1:4 AOH1996: Hypromellose Acetate Succinate AS-MG (HPMC AS-MG) was selected as the SDD formula, and acetone was selected as solvent system for spray drying.

[0207] A clinical dose strength of 150 mg of AOH1996 was selected, and two prototype batches were produced to assess feasibility. One formulation was selected to move forward for scale-up and manufacturing of a demo batch according to in vivo pharmacokinetic (PK) result and process study, and followed with clinical trial materials (CTM) manufacturing.

[0208] The major processes of AOH1996 tablets 150 mg consisted of spray drying, pre- blending, roller compaction, blending / lubrication, tablet compression, coating, bottling, and labeling. The manufacturing process flow chart is shown in FIG.2.

[0209] Description and Composition (AOH1996, Tablet, 150 mg)

[0210] Table 8. General information for AOH1996 Drug AOH1996Dosa e Form Tablet for oral administration

[0211] Pharmaceutical Development

[0212] Components of the drug (AOH1996 tablet, 150 mg)

[0213] The final drug product consists of AOH1996 drug substance and excipients as listed in Table 9. The original formulation of the drug was softgel capsules. However, the product has been reformulated to increase drug load and minimize the number of tablets required per dose.

[0214] Table 9. Summary of API and Excipients Function API Active Ingredient AOH1996aGe

[0215] Drug Product

[0216] Formulation Development

[0217] Formulation development was performed at WuxiSTA.

[0218] Physiochemical and Biological Properties

[0219] Physical characteristics of the GMP clinical trial material are summarized in Table 10.

[0220] Table 10. Summary of the physical characteristics of CTM batch tablets Batch No. GMP BatchKorsch XM-12 4 sets of 2092*991 mm 0-Max 29.26Min 23.45M 2 24

[0221] Container / Closure System

[0222] Packaging materials are selected in agreement with FDA requirements for oral tablets providing protection from light and water vapors, with low likelihood of interacting with its container closure system components and intended for repeat use.

[0223] The tablets are packaged and stored in HDPE bottles (100 mL) equipped with one 2 g can dessicant, 38 mm child resistant cap, and foil induction seal. Table 11 provides the details of the storage container components.

[0224] Table 11. Container closure components Components Manufacturer Part Number HDPE bottle 100 ml Sanner GmbH B100-3

[0225] The AOH1996 tablets will be stored at 25 ± 2 ºC isolated from any associated or unassociated project.

[0226] Microbiological Attributes

[0227] The drug product is evaluated for microbial limits and must meet specifications for release. The storage conditions as well as the vials prevent microbial contamination of the drug product.

[0228] Batch Formula

[0229] The formulation summary for 150 mg dose strength tablets is provided in Table 12.

[0230] Table 12. Formulation summary AOH1996150 mg Tablet Dose strength: 150 mg i i n t)

[0231] Description of Manufacturing Process and Process Controls (AOH1996, tablet, 150 mg)

[0232] The process flow diagram for manufacture of AOH1996 tablets (150 mg) is provided in FIG.2. A brief description of each manufacturing step follows.

[0233] Spray Dried Dispersion of AOH1996 API

[0234] Preparation of blank solvent and addition of API. Acetone is charged into the solution preparation tank. AOH1996 API is slowly added into the acetone under continuous stirring at 150 ± 50 rpm at room temperature for at least 15 minutes until API is dissolved and a clear solution is achieved.

[0235] Addition of HPMC AS-MG. HPMC AS-MG is charged into the API solution preparation vessel and continuously stirred at 150 ± 50 rpm for at least two hours until mixture is a yellow-ish opalescent solution free of particulates.

[0236] Solution filtration. The solution is then filtered through a 50 µm filter to the feed tank.

[0237] Spray drying. The spray dryer is assembled and prepared by warming up and then spraying blank solvent to achieve target parameters. The spray drying process is performed until all solution is consumed. Blank solvent is sprayed for at least 15 minutes after each sublot solution is finished in order to collect additional spray dried dispersion in the system. Collected spray dried dispersion is dried simultaneously with the vacuum tray dryer while spray drying is ongoing.

[0238] Secondary drying. The collected wet spray dry dispersion is charged in the vacuum tray dryer for secondary drying and dried at 45 (40~55) °C. Every two hours, the SDD is raked and lumps are removed with a single-use power scraper. Samples are taken to evaluate for acetone residual solvent after 4, 6, and 8 hours of drying time for sublot 1; at 8 hours drying time for sublot 2; and at 6 hours drying time for sublots 3-8. Residual acetone should be less than 450 ppm.

[0239] Vacuum drying of sublots is performed in succession from completion of drying of the prior lot.

[0240] Drug Product Formulation Process

[0241] Pre-blending

[0242] Microcrystalline cellulose PH-102 is weighed into a colloidal silicon dioxide aerosol 200 pharma bag at 10x the weight of the bag and mixed for 1-2 minutes. The mixture is passed through comil and collected into one low density polyethylene (LDPE) bag. Remaining microcrystalline cellulose PH-102, croscarmellose sodium SD-711 and mannitol 100SD are passed through comil sequentially and the mixture is collected into another LDPE bag.

[0243] Milled materials and Spray Dried Dispersion of AOH1996: HPMC AS-MG (1:4) are charged into the bin in the following order: 1. Microcrystalline cellulose PH-102 and colloidal silicon dioxide aerosol 200 pharmamixture 2. Spray Dried Dispersion of AOH1996: HPMC AS-MG (1:4)3. Croscarmellose sodium and mannitol 100SD mixture

[0244] The contents of the bin are blended at 10 rpm for approximately 10 minutes and collected into double LDPE bags.

[0245] Milling – blended material

[0246] The Comil is set up to U10: 1400 (1150-1650) and the mixture from the blending step is milled.

[0247] Blending and Sieving

[0248] The mixture from the above milling step is charged into a bin again and blended at 10 rpm for approximately 20 minutes.

[0249] A 60 mesh screen is used to sieve the intra Magnesium Stearate LIGAMED MF- 20V-MB and stored in double LDPE bags and labeled accordingly. The intra Magnesium Stearate LIGAMED MF-20V-MB is weighed per batch formula and actual weight value is recorded.

[0250] The re-weighed intra Magnesium Stearate LIGAMED MF-20V-MB is charged into a bin and blended at 10 rpm for approximately 10 minutes.

[0251] Approximately 40 g of the mixture is taken from the bin for evaluation / information only for powder weight, volume and bulk density and then discarded as waste.

[0252] The remaining mixture from the bin is discharged into double LDPE bags.

[0253] Roller Compaction

[0254] Pre-blended material undergoes roller compaction on WP120. Ribbons are prepared with 4 MPa roller compaction pressure. During the roller compaction process, ribbons are screened through a granulation screen to produce granules.

[0255] Approximately 110 g of granule samples are taken after the roller compaction step to evaluate granule weight, volume, and bulk density.

[0256] Tablet Compression

[0257] Tablet cores are compressed using a XM-12 rotary tablet press. The tablet press is set up with a force feeder and four sets of compression tolling. Tablets are evaluated on a regular basis for tablet weight, hardness, thickness, friability, disintegration time and appearance. Tablets are collected into double LDPE bags with 200 g desiccants and loosely tied. Appearance of the tablets and punches after compression is recorded and inspected for abnormalities. Composite bags (aluminum bags) are heat sealed and labelled accordingly. The aluminum bags are then inserted in closed containers.

[0258] Coating

[0259] The tablets are coated in two sublots, using a 56 L coating pan and two spray guns. Coating parameters are adjusted as needed to maintain a Bed Temperature within 38 °C – 50 °C and coated until the weight gain per 20 tablets is approximately 3.0% (2.5%–4.0%).

[0260] Bottle Packaging

[0261] AOH1996 tablets are packaged into HDPE bottles and labelled manually.

[0262] Controls of Critical Steps and Intermediates (AOH1996 tablets, 150 mg)

[0263] Process Validation and / or Evaluation (AOH1996, Tablets, 150mg)

[0264] Control of Excipients

[0265] Excipients are commercially sourced, most of which meet USP / NF and / or EP regulations.

[0266] Control of AOH1996 Drug Product

[0267] Specifications

[0268] Specifications for AOH1996150 mg tablets is provided in Table 13.

[0269] Table 13. AOH1996, 150 mg Release Tests and Specifications Release Test Specification Appearance Orange oval film coated tableteExample 4: Pharmacokinetics

[0270] An in vivo pharmacokinetics (PK) analysis was conducted in male beagle dogs to compare a single dose of spray-dried dispersion-based AOH1996 tablets and the original softgel capsule formation. Results are presented in Table 14. Under the similar nominal dose (160 mg versus 150 mg), the tablets showed comparable PK results with the softgels.

[0271] Table 14. Pharmacokinetic results of AOH1996 tablets Batch No. FP285502-P22001 D-FP319201-T23001 A1 API HPM A M 14)Example 5: Clinical study and pharmacokinetic results

[0272] A clinical study was conducted in 10 patients and the PK properties of two formulations were evaluated. Patients received doses twice daily over a 28-day period. ^ Patients #1-6 (Softgel): Patients 1-6 (Pt #1-6) received an escalating doses of AOH1996 in the Softgel capsule formulation, Pt #1: 120 mg / dose; Pt #2: 240 mg / does; Pt #3: 480 mg / dose; and Pt #4-6: 960 mg / dose. Each capsule contained 40 mg of AOH1996 API in a liquid mixture of 840 mg of Kolliphor EL and 120 mg of Poloxamer P124. ^ Patients #7-10 (Tablet): Pt #7-10 all received the new tablet formulation at 900 mg of AOH1996 per administration.

[0273] Plasma concentrations of AOH1996 were measured at multiple time points after dosing on day 1 and day 8 (FIG.4).

[0274] Results: The new tablet formulation demonstrated significantly improved bioavailability compared to the softgel capsule, even at a lower administered dose of the API.

[0275] As shown in FIG.5, the tablet formulation resulted in superior pharmacokinetic parameters: ^ Higher Exposure: The tablet formulation administered at a 900 mg dose of AOH1996 achieved a higher maximum plasma concentration (Cmax) and a greater total drug exposure (AUC) than the softgel formulation administered at a 960 mg dose. ^ Improved PK Profile: The new tablet formulation also led to a longer half-life (T1 / 2) and a delayed time to reach maximum concentration (Tmax), indicating a more sustained absorption profile.

[0276] Accordingly, the specific combination of excipients and the use of an amorphous solid dispersion in the tablet formulation significantly increases unit drug load and enhances the oral bioavailability of AOH1996, allowing for improved therapeutic efficacy at a reduced dosage.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof; excipient is hydroxypropyl2. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of the compound is 150 mg.

3. The pharmaceutical composition of claim 1, wherein the compound is in a non-crystalline state with the hydroxypropyl methylcellulose.

4. The pharmaceutical composition of claim 1, wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose acetate succinate, medium grade granule (HPMC AS-MG).

5. The pharmaceutical composition of claim 1, further comprising a sweetener, a disintegrant, a stabilizer, a thickening agent, and a tableting agent.

6. The pharmaceutical composition of claim 5, wherein the sweetener is mannitol.

7. The pharmaceutical composition of claim 5, wherein the disintegrant is croscarmellose sodium.

8. The pharmaceutical composition of claim 5, wherein the stabilizer is colloidal silicon dioxide.

9. The pharmaceutical composition of claim 5, wherein the thickening agent is hydroxypropyl cellulose.

10. The pharmaceutical composition of claim 5, wherein the tableting agent is magnesium stearate.

11. The pharmaceutical composition of claim 1, comprising 62.5% by weight of the compound in a non-crystalline state with the hydroxypropyl methylcellulose, 13.5% by weight of microcrystalline cellulose, 13.5% by weight of mannitol, 5% by weight of croscarmellose sodium, 1% by weight of colloidal silicon dioxide, 3% by weight of hydroxypropyl cellulose, and 1.5% by weight of magnesium stearate.

12. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in a spray-dried dispersion-based tablet form.

13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the formula: a pharmaceutically acceptable salt thereof;amount is 150 mg; and wherein the pharmaceutical composition is in a tablet form suitable for human oral administration.

14. The pharmaceutical composition of claim 13, wherein the dimensions of the tablet are about 21 mm in length, about 10 mm in width, and about 7 mm in height.

15. The pharmaceutical composition of claim 13, wherein the dimensions of the tablet are 20.92 mm in length, 9.91 mm in width, and 7.2 mm in height.

16. The pharmaceutical composition of claim 13, wherein the pharmaceutically acceptable excipient is hydroxypropyl methylcellulose acetate succinate, medium grade granule (HPMC AS-MG).

17. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is in a spray-dried dispersion-based tablet form.

18. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject the pharmaceutical composition of any one of claims 1 to 17.

19. The method of claim 18, wherein the pharmaceutical composition is administered twice daily.

20. The method of claim 19, wherein 6 to 15 tablets of the pharmaceutical composition are administered twice daily.

21. The method of claim 20, wherein 6 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 1,800 mg.

22. The method of claim 20, wherein 7 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,100 mg.

23. The method of claim 20, wherein 8 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,400 mg.

24. The method of claim 20, wherein 9 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 2,700 mg.

25. The method of claim 20, wherein 10 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,000 mg.

26. The method of claim 20, wherein 11 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,300 mg.

27. The method of claim 20, wherein 12 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,600 mg.

28. The method of claim 20, wherein 13 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 3,900 mg.

29. The method of claim 20, wherein 14 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 4,200 mg.

30. The method of claim 20, wherein 15 tablets of the pharmaceutical composition are administered twice daily, and wherein the total therapeutically effective amount of the compound is 4,500 mg.

31. The method of claim 18, wherein said cancer is a solid tumor.

32. The method of claim 18, wherein said cancer is a lung cancer, colon cancer, central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, mesothelioma, liver cancer, stomach cancer, esophageal cancer, bladder cancer, cervical cancer, osteosarcoma, pancreatic cancer, adrenal cortical cancer, adrenal gland cancer, colorectal cancer, testicular cancer, myeloma, B-acute lymphoblastic lymphoma, non- Hodgkin’s lymphoma, Hodgkin’s lymphoma, chronic leukemia, acute leukemia, glandular carcinoma, or hematoid carcinoma.

33. The method of claim 18, wherein said cancer is acute myeloid leukemia, pancreatic cancer, or osteosarcoma.

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